The toxicogenomics research program at the University of North Carolina-Chapel Hill (UNC-CH) is focused on genetic determinants of susceptibility to environmental toxicants and chemotherapeutic drugs. Human and murine model systems will be used to determine the patterns of alterations in gene expression when cells and animals are exposed to several classes of toxins. Toxin classes under study include agents that induce oxidative stress, DNA double strand breaks, alkylation of DNA bases, as well as nuclear receptor agonists. cDNA microarrays containing greater than 10,000 expressed genes will be used to determine for human cells and mice, the dose and time kinetics of toxicant-induced changes in gene expression. In two interactive research projects diploid human mammary epithelial cells, fibroblasts and lymphoblasts, will be treated with doses of toxicants ranging about the mean lethal dose (D/o for inactivation of colony formation). Cell lines with heterozygous and homozygous mutations in the tumor suppressor genes p53, ATM and BRCA1, or with genetic inactivation of suppressor function, will be compared to wildtype lines to establish profiles of genetic susceptibility to toxicant stress. Similarly, a third research project will determine patterns of response to the toxicants in liver, mammary gland and colon of ten strains of mice with varying susceptibilities to carcinogenesis. These studies will determine whether murine strain-dependent susceptibility to carcinogenesis resembles human genetic susceptibility due to mutations in tumor suppressors. A Toxicology Resource Core proposes a demonstration project to determine the profiles of altered gene expression in livers of mice exposed to non-genotoxic chemicals which activate the nuclear receptors, AhR, CAR and PPAR-alpha. The three research projects and the Toxicology Resource Core will be served by an Administrative Core, a Microarray Facility Core, and an lnformatics Facility Core. The UNC-CH toxicogenomics research program has the scientific expertise and organizational infrastructure to provide significant and substantial benefits to the Toxicogenomics Research Consortium.